E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Late Metachromatic Leukodystrophy (MLD) |
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E.1.1.1 | Medical condition in easily understood language |
Metachromatic leukodystrophy, the most common form of leukodystrophy, is a rare inherited neurometabolic disorder affecting the white matter of the brain (leukoencephalopathy). |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067609 |
E.1.2 | Term | Metachromatic leukodystrophy |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the effects of intrathecal (IT) administration of SHP611 on the time to loss of locomotion, as indicated by category 5 or higher in the Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) compared with external control group data in children with late infantile MLD.
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E.2.2 | Secondary objectives of the trial |
- To evaluate the effects of IT administration of SHP611 on subjects who experience decline in gross motor function as indicated by GMFC-MLD category 5 or higher, compared with matched external control group data in children with MLD - To evaluate the effects of IT administration of SHP611 on the decline in gross motor function, as measured by an unreversed decline in GMFC-MLD of more than 2 categories compared with matched external control group data in children with MLD, time course of declining gross motor function using the GMFC-MLD, and change from baseline of gross motor function, using the GMFC-MLD - To evaluate the effects of IT administration of SHP611 on cerebrospinal fluid (CSF) sulfatides (pharmacodynamic [PD] biomarker) - To evaluate the effects of IT administration of SHP611 on gross motor function, using the Gross Motor Function Measure 88 (GMFM-88) total score in children with MLD
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients must meet all of the following criteria to be considered eligible for inclusion as a subject in the study:
1. The subject must have a documented diagnosis of MLD (Groups A-E) • Low ASA activity in leukocytes (compared to laboratory normal range) AND • Elevated sulfatides in urine
2. The subject must have a gait disorder due to spastic ataxia or weakness attributable to MLD by the investigator and documented by a primary care physician or a specialist physician by 30 months of age (Groups A-C, and F), or be minimally symptomatic and ≥6 to <18 months of age (Group D), or be early symptomatic and ≥12 to <18 months of age (Group E). Subjects in Group E must have neurological symptoms documented by either a primary care physician or a specialist physician.
3. The subject’s age at the time of informed consent, must be: • Group A: 18 to 48 months of age • Group B: 18 to 72 months of age • Group C: 18 to 72 months of age • Group D: ≥6 to <18 months of age • Group E: ≥12 to <18 months of age • Group F: 18 to 72 months of age
4. The subject’s GMFC-MLD category at screening must be: • Group A: GMFC-MLD category of 1 or 2 • Group B: GMFC-MLD category of 3 • Group C: GMFC-MLD category of 4 • Group D: minimally symptomatic, and has the same ASA allelic constitution as an older sibling with confirmed late infantile or juvenile onset MLD • Group E: early symptomatic, ≥12 to <18 months of age with a GMFC-MLD category of 1 or 2, and with a history of achieving stable walking (defined as at least 1 month of independent walking) • Group F: GMFC-MLD category of 5 or 6
5. The subject and his/her parent/representative(s) must have the ability to comply with the clinical protocol.
6. Subject's parent or legally authorized representative(s) must provide written informed consent prior to performing any study-related activities. Study-related activities are any procedures that would not have been performed during normal management of the subject.
Inclusion and exclusion criteria for the matched historical controls will be provided in the Statistical Analysis Plan (SAP). |
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E.4 | Principal exclusion criteria |
1. Multiple sulfatase disorder as determined by abnormal activity of another lysosomal sulfatase (based upon the reference laboratory’s normal range) or a known genetic disorder other than MLD
2. History of bone marrow transplant (BMT), hematopoietic stem cell transplantation (HSCT), or gene therapy or undergoes BMT, HSCT, or gene therapy at any point during the study
3. Primary presentation of MLD was behavioral or cognitive symptoms (per investigator’s clinical judgment); behavioral symptoms that are secondary to motor deficits (eg: tantrums in response to loss of motor skills) are not exclusionary.
4. The subject has any known or suspected hypersensitivity to agents used for anesthesia or has history of difficult airway or potential for airway compromise
5. Any other medical condition or serious comorbid illness that in the opinion of the investigator would preclude participation in the study
6. Subjects with laboratory, ECG, or vital sign abnormalities reflecting intercurrent illness that may compromise their safety during the trial should not be enrolled. Abnormal laboratory, vital sign and ECG results at screening should be reviewed with the Takeda medical monitor.
7. The subject is enrolled in another clinical study that involves use of any investigational product (drug or device) within 30 days or 5 half-lives (whichever is longer) prior to study enrollment or at any time during the study
8. The subject has had prior exposure to SHP611
9. The subject must weight > 11lbs (5kg)
10. The subject has a condition that is contraindicated as described in the SOPH-A-PORT Mini S IDDD Instructions for Use a. The subject has had, or may have, an allergic reaction to the materials of construction b. The subject has shown an intolerance to an implanted device c. The subject’s body size is too small to support the size of the SOPH-A-PORT Mini S Access Port d. The subject’s drug therapy requires substances known to be incompatible with the materials of construction e. The subject has a known or suspected local or general infection f. The subject is at risk of abnormal bleeding due to a medical condition or therapy g. The subject has one or more spinal abnormalities that could complicate safe implantation or fixation h. The subject has a functioning CSF shunt device
Filtering criteria for the selection of the matched external control group will be provided in the Statistical Analysis Plan (SAP). |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is time to loss of locomotion, measured by progression to GMFC-MLD category 5 or higher, or death, whichever occurs first, up to Week 106, evaluated on subjects in Group A. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints of this study are: • Response in Group A, defined as maintenance of gross motor function at Week 106, evaluated as subjects who do not experience any event within Week 106, where event is defined as a decline in GMFC MLD to category 5 or higher, or death • Decline in gross motor function using GMFC MLD: - Change from baseline at Week 106 and EOS in gross motor function, using the GMFC MLD - Subjects with unreversed decline from baseline in GMFC-MLD of more than 2 categories, defined as any decline of more than 2-categories that has not reverted to a 2-category decline (or better) at Week 106, evaluated on subjects in Group A - Time to unreversed decline from baseline in GMFC-MLD of more than 2 categories, defined as any decline of more than 2-categories that has not reverted to a 2-category decline (or better) as of the last recorded observation • Change from baseline at Week 106 and EOS in CSF sulfatides levels • Response in Group A, defined as maintenance of gross motor function at Week 106, defined as a GMFM 88 total score ≥40 • Decline in gross motor function using GMFM-88: - Time to unreversed decline from baseline at Week 106 and EOS in GMFM-88 total score decrease of >20 points or unreversed decline to a score <40 points, whichever occurs first - Change from baseline at Week 106 and EOS in gross motor function, using the GMFM-88 total score - Subjects in Group A with GMFM-88 total score decrease of ≤20 points from baseline and a total score that is ≥40 at Week 106 and EOS • Change from baseline at Week 106 and EOS in expressive language using the ELFC-MLD |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Brazil |
Canada |
Israel |
Japan |
United States |
Belgium |
France |
Germany |
Greece |
Italy |
Netherlands |
Spain |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The Study Completion Date is defined as the date on which the last subject in the study completes the final protocol-defined assessment(s). This includes the follow-up visit or contact, whichever is later. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |